Summary of work:Sonodynamic therapy is a promising new modality for cancer treatment based on the synergistic effects of cell killing by a combination of sonosensitzer and ultrasound. Ultrasound can penetrate deeply into tissue and can be focused in a small region of tumor to activate non-toxic molecules (e.g. porphyrins ) thus minimizing undesirable side effects. The experimental evidence suggests that sonosensitization is due to the chemical activation of sonosensitizers inside or in close vicinity of hot collapsing cavitation bubbles to form sensitizer-derived radicals either by direct pyrolysis of the sensitizer at the water-gas interface or due to the reactions of hydrogen atoms and hydroxyl radicals formed by the pyrolysis of water. The free radicals derived from the sonosensitizer (mostly carbon-centered) react with oxygen to form peroxyl and alkoxyl radicals. Unlike OH radicals and H atoms which are formed by pyrolysis inside cavitation bubbles, the reactivity of alkoxyl and peroxyl radicals with organic compounds in biological media is much lower and hence they have a higher probability of reaching critical cellular sites.The synergistic effect of ultrasound (47 kHz) and analogues of gallium-porphyrin derivatives (ATX-70) on cytolysis of human leukemia cells (HL-525 and HL-60) suspended in a cell culture medium were studied. Organic surfactants preferentially accumulate and subsequently decompose at the gas/solution interface of cavitation bubble, producing secondary radicals that can diffuse to the bulk solution. The gallium porphyrin analogues used in the current study possessed two n-alkyl side chains (ATX-Cx, where x = number of carbon atoms, ranging from x = 2 to x = 12). By varying the n-alkyl chain length, thereby modifying the surfactant properties of the ATX-Cx derivatives, cell killing in relation to the accumulation of the ATX-Cx derivatives at the gas/solution interface of cavitation bubbles was determined. Following sonolysis in the presence of the ATX-Cx, a strong correlation for the yield of carbon centered radicals and cell killing was observed. These results support the hypothesis that a sonochemical mechanism is responsible for the synergistic effect of ultrasound and ATX-Cx on HL-525 and HL-60 cells. Studies of the ultrasound-induced apoptosis and lysis of U937 cells by a hypotonic medium support the hypothesis that non-lethal hypotonia can enhance ultrasound-induced cell-killing. Ultrasound-induced killing of U937 cells was enhanced by azobis(2-amidinopropane)dihydrochloride. These findings suggest the clinical potential of temperature-dependent free radical generators in cancer therapy by ultrasound. The mechanism of sonodynamic therapy is probably not governed by a universal mechanism, but may be influenced by multiple factors including the nature of the biological model, the sonosensitizer and the ultrasound prameters.1.Ogawa, R.; Kondo, T.; Mori, H.; Zhao, Q.L.; Fukuda, S.; Riesz, P.: Effects of dissolved gases on ultrasound mediated in vitro gene transfection. Ultrasonics Sonochemistry, 9, 197-203, 2002.2.Feril, L.B.; Kondo, T.; Umemura, S.; Tachibana, K.; Manalo, A.H.; Riesz, P.: Sound waves and antineoplastic drugs: The possibility of an enhanced combined anticancer therapy. J.Med.Ultrasonics(Japan), 29, 173-187, 2002.3.Sostaric, J.Z. and Riesz, P.: Adsorption of surfactants at the gas/solution interface of cavitation bubbles: An ultrasound intensity independent frequency effect in sonochemistry. J. Phys. Chem. B., 106, 12537-12548, 2002.4.Miyoshi, N.; Sostaric, J.Z.; Riesz, P.: Correlation between sonochemistry of surfactant solutions and human leukemia cell killing by ultrasound and porphyrins. Free Rad. Biol. Med., 34, 710-719, 2003.